UNIPROT:P05412 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophage inflammatory protein-2 (MIP-2) is a C-X-C chemokine that is important in recruiting neutrophils to inflammatory sites. Our previous reports demonstrated that lipopolysaccharide (LPS) or CpG-oligode-oxynucleotide (CpG-ODN) rapidly induce MIP-2 gene expression in the macrophage cell line, RAW 264.7. Here, we show that the DNA sequence of the MIP-2 promoter between -114 and +14 is sufficient for strong promoter activity in LPS- or CpG-ODN-stimulated RAW 264.7 cells. Importantly, comprehensive mutant analysis reveals that an Sp1 element in the promoter region between -114 and -94 is essential for synergistic MIP-2 promoter activation by NF-kappaB and c-Jun regardless of the presence of an AP-1 site. By combining deletion or site-specific mutant analysis with immunocomplex assays, we also confirmed that Sp1 mediates the recruitment of transcription factors NF- kappaB and c-Jun in LPS- or CpG-ODN-treated RAW 264.7 cells. Several lines of experimental evidence imply that the Sp1-binding element is an important determinant of MIP-2 promoter activity, and that NF-kappaB, c-Jun and Sp1 can functionally cooperate to elicit maximal activation of the promoter.
...
PMID:Sp1-associated activation of macrophage inflammatory protein-2 promoter by CpG-oligodeoxynucleotide and lipopolysaccharide. 1566 90

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) enhances reepithelialization in wounds. Estrogen is known to promote cutaneous wound repair. We examined the in vitro effects of 17beta-estradiol (E2) on HB-EGF production by human keratinocytes. E2 or membrane-impermeable BSA-conjugated E2 (E2-BSA) increased HB-EGF secretion, mRNA level, and promoter activity in keratinocytes. E2 or E2-BSA enhanced in vitro wound closure in keratinocytes, and the closure was suppressed by anti-HB-EGF antibody. Activator protein-1 (AP-1) and specificity protein 1 (Sp1) sites on HB-EGF promoter were responsible for the E2- or E2-BSA-induced transactivation. Antisense oligonucleotides against c-Fos, c-Jun, and Sp1 blocked E2- or E2-BSA-induced HB-EGF transactivation. E2 or E2-BSA enhanced DNA binding and transcriptional activity of AP-1 and generated c-Fos/c-Jun heterodimers by inducing c-Fos expression. E2 or E2-BSA enhanced DNA binding and transcriptional activity of Sp1 in parallel with the enhancement of Sp1 phosphorylation. These effects of E2 or E2-BSA were not blocked by the nuclear estrogen receptor antagonist ICI-182,780 or anti-estrogen receptor-alpha or -beta antibodies but were blocked by inhibitors of G protein, phosphatidylinositol-specific PLC, PKC-alpha, and MEK1. These results suggest that E2 or E2-BSA may enhance HB-EGF production via activation of AP-1 and Sp1. These effects of E2 or E2-BSA may be dependent on membrane G protein-coupled receptors different from nuclear estrogen receptors and on the receptor-mediated activities of phosphatidylinositol-specific PLC, PKC-alpha, and MEK1. E2 may enhance wound reepithelialization by promoting HB-EGF production in keratinocytes.
...
PMID:17beta-estradiol enhances heparin-binding epidermal growth factor-like growth factor production in human keratinocytes. 1576 Dec 12

Expression of the tissue inhibitor of metalloproteinases-1 (Timp-1) gene can be induced by either phorbol myristate acetate (PMA) or transforming growth factor beta1 (TGF-beta1), although the signalling pathways involved are not clearly defined. Canonically, histone deacetylase inhibitors (HDACi) such as trichostatin A (TSA) or sodium butyrate (NaB) increase total cellular histone acetylation and activate expression of susceptible genes. Remarkably, PMA and TGF-beta1 stimulation of Timp-1 show a differential response to TSA or NaB. TSA or NaB potentiate PMA-induced Timp-1 expression but repress TGF-beta1-induced Timp-1 expression. The repression of TGF-beta1-induced Timp-1 by TSA was maximal at 5 ng.mL(-1), while for the superinduction of PMA-induced Timp-1 expression, the maximal dose is > 500 ng x mL(-1) TSA. A further HDACi, valproic acid, did not block TGF-beta1-induced Timp-1 expression, demonstrating that different HDACs impact on the induction of Timp-1. For either PMA or TGF-beta1 to induce Timp-1 expression, new protein synthesis is required, and the induction of AP-1 factors closely precedes that of Timp-1. The effects of the HDACi can be reiterated in transient transfection using Timp-1 promoter constructs. Mutation or deletion of the AP-1 motif (-59/-53) in the Timp-1 promoter diminishes PMA-induction of reporter constructs, however, the further addition of TSA still superinduces the reporter. In c-Jun-/- cells, PMA still stimulates Timp-1 expression, but TSA superinduction is lost. Transfection of a series of Timp-1 promoter constructs identified three regions through which TSA superinduces PMA-induced Timp-1 and we have demonstrated specific protein binding to two of these regions which contain either an avian erythroblastosis virus E26 (v-ets) oncogene homologue (Ets) or Sp1 binding motif.
...
PMID:Differential effects of histone deacetylase inhibitors on phorbol ester- and TGF-beta1 induced murine tissue inhibitor of metalloproteinases-1 gene expression. 1581 85

Tumor cell expression of COX-2 has been implicated in the progression of murine and human lung cancer. Inhibition of COX-2 by nonsteroidal antiinflammatory drugs reduces the risk of cancer development in humans and suppresses tumor growth in animal models. However, the underlying mechanisms for this beneficial effect are not fully understood. Here we explore the potential link between the anticancer effects of COX-2 inhibitors and the expression of the integrin alpha5beta1. Expression of this integrin in carcinoma cells is associated with invasiveness and malignant progression. This, together with our studies showing that fibronectin, the ligand of alpha5beta1, stimulates the growth of human lung carcinoma cells, and that this effect is mediated through alpha5beta1-dependent signals, has prompted us to examine the effects of COX-2 inhibitors on alpha5beta1 expression in human non small cell lung carcinoma (NSCLC) cells. We found that the selective COX-2 inhibitors NS398 and Nimesulide decreased mRNA expression and protein production of the integrin alpha5 subunit. This effect was associated with inhibition of NSCLC cell adhesion to fibronectin. The COX-2 inhibitors triggered the phosphorylation of extracellular signal-regulated kinase (Erk) in a time-dependent manner, and the inhibitor of Mek-1/Erk PD98095 prevented their inhibitory effects on integrin alpha5 expression. Transient transfection assays showed that the COX-2 inhibitors affected integrin alpha5 gene transcription by acting between -92 to -41 bp of the human integrin alpha5 gene promoter. Gel mobility shift assays showed that the COX-2 inhibitors increased Sp1 DNA binding, but decreased that of AP-1. These effects were accompanied by an increase in Sp1 protein and a decrease in c-Jun protein expression, as well as inhibition of SAPK/JNK phosphorylation. The Sp1 inhibitor, Mithramycin A, also blocked the inhibitory effect of the COX-2 inhibitors on alpha5 expression and promoter activity. Overall, these findings suggest that COX-2 inhibitors suppress alpha5beta1 integrin expression in NSCLC through effects on integrin alpha5 gene transcription mediated by Erk activation, increased Sp1, decreased AP-1 DNA binding and inactivation of SAPK/JNK signals. Our observations unveil a new mechanism of action against NSCLC for COX-2 inhibitors that relates to regulation of integrin alpha5 gene expression and, consequently, recognition of extracellular matrices (i.e., fibronectin) by tumor cells. (c) 2005 Wiley-Liss, Inc.
...
PMID:COX-2 inhibitors suppress integrin alpha5 expression in human lung carcinoma cells through activation of Erk: involvement of Sp1 and AP-1 sites. 2625 13

The signal transduction of human 12(S)-lipoxygenase and the regulation of gene activation, induced by epidermal growth factor (EGF), are discussed in this review article. Treatment of human epidermoid carcinoma A431 cells with EGF induces the gene expression of human 12(S)-lipoxygenase, and two Sp1 binding sites residing at -158 to -150 bp and -123 to -114 bp are essential in the mediation of EGF induction of the 12(S)-lipoxygenase gene. EGF induces MAPK activation in cells, followed by the activation of AP1. Thus, the biosynthesis of c-Jun is enhanced, which subsequently interacts with Sp1. c-Jun on Sp1/c-Jun complex is then recruited to gene promoter through the binding of Sp1 to Sp1-binding sites on gene promoter. Subsequent transactivation of the promoter activation of the human 12(S)-lipoxygenase gene is induced. In addition to the functional role of Sp1 in gene regulation of 12(S)-lipoxygenase, recent studies have also demonstrated that Sp1 acting as an anchor protein to recruit transcription factor c-Jun is essential for growth factor and/or phorbol ester-induced expression of several genes.
...
PMID:Transcription factor Sp1 functions as an anchor protein in gene transcription of human 12(S)-lipoxygenase. 1612

Nectin-2, a major protein component of the adherens junctions (AJs), is found between Sertoli cells and germ cells in the seminiferous epithelium. Recent studies have shown that the expression of nectin-2 gene in testis is crucial to maintain normal spermatogenesis since male knockout mice lacking nectin-2 gene are sterile and possess morphologically abnormal spermatozoa. However, the molecular mechanisms governing its basal transcription remain poorly understood. By the use of Sertoli and germ cell-lines (TM4 and GC-2spd(ts) cells, respectively) in transient transfection studies, we showed that the minimal mouse nectin-2 promoter was located between nucleotides -316 and -211 (relative to the translation start site). Two putative Sp1 motifs and one each of the CRE, AP1, and AP2 motifs were identified within this region. Mutational studies showed that these two Sp1 motifs cooperated synergistically with the CRE motif, but not the AP1 and AP2 motifs, to regulate nectin-2 gene transcription in both TM4 and GC-2spd(ts) cells. By EMSAs, we found that an AP-1 consensus sequence was able to inhibit DNA-protein complex formation with the CRE motif, suggesting an interaction between the AP-1 transcription factor (c-Jun) and CREB within the CRE motif. Overexpressions of CREB and c-Jun, but not c-Fos, also significantly increased the promoter activity, which suggests that CREB and c-Jun are the crucial transcription factors involved in regulating nectin-2 gene transcription. Chromatin immunoprecipitation assay has shown that, in vivo, CREB, c-Jun, and Sp1 family proteins are bound to the mouse nectin-2 promoter. Analysis of the staged tubules has confirmed that the cyclic expressions of CREB and nectin-2 coincide with the event of adherens junction restructuring between Sertoli cells and germ cells. The cross-talk between CREB, c-Jun, and Sp1 family protein is believed to be a major transcription machinery to drive nectin-2 expression in Sertoli cells.
...
PMID:Nectin-2 expression in testicular cells is controlled via the functional cooperation between transcription factors of the Sp1, CREB, and AP-1 families. 1625 13

Inflammatory responses stimulated by bacterial endotoxin LPS involve Ca2+-mediated signaling, yet the cellular sensors that determine cell fate in response to LPS remain poorly understood. We report that exposure of RAW 264.7 macrophage-like cells to LPS induces a rapid increase in CaM abundance, which is associated with the modulation of the inflammatory response. Increases in CaM abundance precede nuclear localization of key transcription factors (i.e., NF-kappaB p65 subunit, phospho-c-Jun, Sp1) and subsequent increases in the proinflammatory cytokine TNF-alpha and inducible nitric oxide synthase (iNOS). Cellular apoptosis after LPS challenge is blocked upon inhibition of iNOS activity using the pharmacological inhibitor 1400W. LPS-mediated iNOS expression and apoptosis also were inhibited by siRNA-mediated silencing of TNF induction, indicating TNF induction both precedes and is necessary for subsequent regulation of iNOS expression. Increasing the level of cellular CaM by stable transfection results in reductions in LPS-induced expression of TNF and iNOS, along with reduced activation of their transcriptional regulators and concomitant protection against apoptosis. Thus the level of CaM available for Ca2+-dependent signaling regulation plays a key role in determining the expression of the proinflammatory and proapoptotic cascade during cellular activation by LPS. These results indicate a previously unrecognized central role for CaM in maintaining cellular homeostasis in response to LPS such that, under resting conditions, cellular concentrations of CaM are sufficient to inhibit the biosynthesis of proinflammatory mediators associated with macrophage activation. Although CaM and iNOS protein levels are coordinately increased as part of the oxidative burst, limiting cellular concentrations of CaM due to association with iNOS (and other high-affinity binders) commit the cell to an unchecked inflammatory cascade leading to apoptosis.
...
PMID:Functional link between TNF biosynthesis and CaM-dependent activation of inducible nitric oxide synthase in RAW 264.7 macrophages. 1642 Dec 3

Telomerase is essential for immortalization of most human cancer cells. Expression of the core telomerase RNA (hTR) and reverse transcriptase (hTERT) subunits is mainly regulated by transcription. However, hTR transcriptional regulation remains poorly understood. We previously showed that the core hTR promoter is activated by Sp1 and is repressed by Sp3. Here, we show that the mitogen-activated protein kinase kinase kinase 1 (MEKK1)/c-Jun-NH(2)-kinase (JNK) pathway represses hTR expression by a mechanism that involves Sp1 and Sp3. Promoter activity was induced by the JNK inhibitor SP600125 and was repressed by activated MEKK1. Repression by MEKK1 was blocked by SP600125 or enhanced by coexpression of wild-type but not phosphoacceptor mutated JNK. SP600125 treatment also increased levels of endogenous hTR. Mutations in the hTR promoter Sp1/Sp3 binding sites attenuated SP600125-mediated promoter induction, whereas coexpression of MEKK1 with Sp3 enhanced hTR promoter repression. Chromatin immunoprecipitation showed that levels of immunoreactive Sp1 associated with the hTR promoter were low in comparison with Sp3 in control cells but increased after JNK inhibition with a reciprocal decrease in Sp3 levels. No corresponding changes in Sp1/Sp3 protein levels were detected. Thus, JNK represses hTR promoter activity and expression, apparently by enhancing repression through Sp3.
...
PMID:Transcriptional repression of telomerase RNA gene expression by c-Jun-NH2-kinase and Sp1/Sp3. 1645 90

We previous reported that Sp1 recruits c-Jun to the promoter of the 12(S)-lipoxygenase gene in 12-myristate 13-acetate-treated cells. We now show that Sp1 that recruited HDAC1 to the Sp1/cJun complex was constitutively acetylated when cells were exposed to phorbol 12-myristate 13-acetate (PMA) (3 h). Prolonged stimulation of the cells with PMA (9 h), however, caused the dissociation of histone deacetylase 1 (HDAC1) and the deacetylation of Sp1, with the latter being able to recruit p300 that in turn caused the acetylation and dissociation of histone 3, thus enhancing the expression of 12(S)-lipoxygenase. We also overexpressed an Sp1 mutant (K703/A, lacking acetylation sites) in the cell and found that cells recruited more p300 and expressed more 12(S)-lipoxygenase. Taken together, our results indicated that Sp1 recruits HDAC1 together with c-Jun to the gene promoter, followed by deacetylation of Sp1 upon PMA treatment. p300 is then recruited to the gene promoter through the interaction with deacetylated Sp1 to acetylate histone 3, leading to the enhancement of the expression of 12(S)-lipoxygenase.
...
PMID:Sp1 deacetylation induced by phorbol ester recruits p300 to activate 12(S)-lipoxygenase gene transcription. 1647 97

The net balance of matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) system has been known to be a key factor in tumor cell invasion. In the present study, we investigated the molecular mechanisms of anti-invasive and antimigrative activity of transforming growth factor (TGF)-beta1 on HT1080 human fibrosarcoma cells. In in vitro Matrigel invasion and Transwell migration assays, TGF-beta1 dose-dependently inhibited the invasion and migration of HT1080 cells, respectively. Gelatin zymography, Western blot, and real-time PCR analysis showed that TGF-beta1 enhanced the expression and secretion of MMP-2, TIMP-1, and, to a lesser degree, MMP-9 but not membrane type 1-MMP and TIMP-2. The addition of recombinant TIMP-1 protein reduced the Matrigel invasion and Transwell migration of HT1080 cells, similar to TGF-beta1. Because augmentation of TIMP-1 might be the major factor for the anti-invasive and antimigrative activity of TGF-beta1, we investigated possible molecular mechanisms responsible for the expression of TIMP-1 induced by TGF-beta1. Treatment of HT1080 cells with TGF-beta1 rapidly phosphorylated three mitogen-activated protein kinases [MAPK; extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun NH2-terminal kinase] and Akt. Among these kinases, the inhibition of only ERK1/2 pathway by PD98059, a specific inhibitor of MAPK/ERK kinase(MEK)-1, and transfection of dominant-negative MEK 1 effectively blocked the TIMP-1 induction by TGF-beta1. Mithramycin, a specific inhibitor of Sp1 transcription factor, but not curcumin, an inhibitor of activator protein-1, and transfection of Sp1 small interfering RNA significantly inhibited the TGF-beta1-induced expression of TIMP-1. In addition, electrophoretic mobility shift assay showed that TGF-beta1 up-regulated Sp1 DNA-binding activity, and PD98059 and mithramycin effectively inhibited these events. Finally, pretreatment of HT1080 cells with PD98059 and mithramycin, but not curcumin, restored the invasive activity of these cells. Taken together, these data suggest that TGF-beta1 modulates the net balance of the MMPs/TIMPs the systems in HT1080 cells for anti-invasion and antimigration by augmenting TIMP-1 through ERK1/2 pathway and Sp1 transcription factor.
...
PMID:Transforming growth factor-beta1 induces tissue inhibitor of metalloproteinase-1 expression via activation of extracellular signal-regulated kinase and Sp1 in human fibrosarcoma cells. 1654 58

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>